Diltiazem formulations and methods of treatment

ABSTRACT

A diltiazem pellet formulation for oral administration comprises a core of diltiazem or a pharmaceutically acceptable salt thereof in association with an organic acid, and a multi-layer membrane surrounding the core and containing a major proportion of a pharmaceutically acceptable film-forming, water insoluble synthetic polymer and a minor proportion of a pharmaceutically acceptable film-forming, water soluble synthetic polymer. The number of layers in the membrane and the ratio of the water soluble to water insoluble polymer being effective to permit release of diltiazem from the pellet at a rate allowing controlled absorption thereof over a twelve hour period following oral administration. The pellet has a dissolution rate in vitro which when measured in a dissolution apparatus (Paddle) according to U.S. Pharmacopoeia XXI in 0.05 M KC1 at pH 7.0 results in not more than 35% of the total diltiazem being released after 2 hours of measurement. Not more than 80% of the total diltiazem is released after six hours of measurement and not less than 85% of the total diltiazem is released after 13 hours of measurement.

This is a continuation of copending U.S. application(s) Ser. No.07/918,925 filed on Jul. 22, 1992, now U.S. Pat. No. 5,219,621.

BACKGROUND OF THE INVENTION

This invention relates to a controlled absorption pharmaceuticalformulation and, in particular, to a controlled absorption form ofdiltiazem for oral administration.

1. Description of the Prior Art

Diltiazem-cis-(+)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzo thiazepin-4-(5H)-one,is a benzothiazine derivative possessing calcium antagonist activity.Diltiazem blocks the influx of calcium ions in smooth and cardiac muscleand thus exerts potent cardio-vascular effects. Diltiazem has been shownto be useful in alleviating symptoms of chronic heart disease,particularly angina pectoris and myocardial ischemia and hypertension,while displaying a low incidence of side effects. Diltiazem isconventionally administered in tablet form as (30 mg or 60 mg) diltiazemhydrochloride sold under the Trade Mark Cardizem (Marion LaboratoriesInc.). Diltiazem in tablet form (30 mg) is also sold under the TradeMark Herbesser (Tanabe Seiyaku). Diltiazem is also sold in capsule form.

Conventional diltiazem therapy starts with 30 mg administered 4 timesdaily. The dosage is gradually increased to 240 mg, given in divideddoses three or four times daily, at one- to two-day intervals until anoptimum response is obtained. Diltiazem is extensively metabolized bythe liver and excreted by the kidneys and in bile. According toprofessional use information issued by Marion Laboratories Inc.,Cardizem is absorbed from the known tablet formulation to about 80% andis subject to an extensive first-pass effect, giving an absolutebioavailability, compared to intravenous administration of about 40%.Single oral doses of 30 to 120 mg of Cardizem result in peak plasmalevels 2-3 hours after administration. Detectable plasma levels occurwithin 30-60 minutes after administration, indicating that Cardizem isreadily absorbed.

The plasma elimination half-life of diltiazem following single ormultiple administration is approximately 3-5 hours. Therapeutic bloodlevels of Cardizem are thought to be in the range of 50-200 ng/ml.

As stated above, conventional diltiazem capsules and tablets areadministered three or four times daily Such frequent drug administrationmay reduce patient compliance and produces irregular blood levels; thusadverse therapeutic effects can arise.

An article by McAuley, Bruce J. and Schroeder, John S. inPharmacotherapy 2: 121, 1982 states that peak plasma levels of diltiazemoccur within one hour with normal capsules and within 3 to 4 hours withsustained release tablets.

Co-pending U.S. patent application Ser. No. 684,661, filed Dec. 20,1984, now U.S. Pat. No. 4,721,619 and incorporated herein by reference,describes and claims an effective diltiazem formulation for twice-dailyadministration.

The formulation is distinguished by a characteristic dissolution ratewhen tested under specified conditions, not least its controlledabsorption characteristics in vivo, which offer distinct advantages overexisting formulations. However, it has been found with certainformulations prepared in accordance with U.S. patent application Ser.No. 684,661, U.S. Pat. No. 4,721,619 when manufactured in productionbatches commensurate with commercial scale manufacture to the indicatedspecifications, that the in vitro performance of the formulationdisimproved beyond acceptable limits when stored over the normallyrequired shelf-life periods. This was found to be particularly the casewith formulations containing the naturally occurring polymer shellac.Our co-pending Patent Application No. . . . , filed simulataneously withthe present Application describes and claims a stable diltiazemformulation for twice-daily administration which includes naturallyoccurring polymers such as shellac. However such naturally occurringpolymers can exhibit considerable variability in quantity and qualitydepending on the source and time of collection and accordingly thereremains a need to produce alternative formulations which do not requiretheir use.

It is an object of the present invention to provide a controlledabsorption diltiazem formulation suitable for twice-dailyadministration, which is bioequivalent to known oral formulations ofdiltiazem, which has good stability over normal shelf-life periods ofeighteen months to two years, and which contains only syntheticpolymeric materials. A further object of the present invention is toimprove the method of manufacture of said formulations.

2. Description of the Invention

Accordingly, the invention provides a diltiazem pellet formulation fororal administration, said pellet comprising a core of diltiazem or apharmaceutically acceptable salt thereof in association with an organicacid, the diltiazem component and the organic acid being present in aratio of from 50:1 to 1:1, and a multi-layer membrane surrounding saidcore and containing a major proportion of a pharmaceutically acceptablefilm-forming, water insoluble, synthetic polymer and a minor proportionof a pharmaceutically acceptable film-forming, water soluble syntheticpolymer, the number of layers in said membrane and the ratio of saidwater soluble to water insoluble polymer being effective to permitrelease of said diltiazem from said pellet at a rate allowing controlledabsorption thereof over a twelve hour period following oraladministration, said rate being measured in vitro as a dissolution rateof said pellet, which when measured in a dissolution apparatus (paddle)according to U.S. Pharmacopoeia XXI in 0.05 M KC1 at pH 7.0substantially corresponds to the following dissolution pattern:

a) from 5 to 35% of the total diltiazem is released after 2 hours ofmeasurement in said apparatus;

b) from 55 to 80% of the total diltiazem is released after 6 hours ofmeasurement in said apparatus;

c) not less than 85% of the total diltiazem is released after 13 hoursof measurement in said apparatus.

Preferably, the diltiazem is in the form of a pharmaceuticallyacceptable salt thereof, more particularly the hydrochloride saltthereof.

The organic acid is preferably represented by one or more of thefollowing acids: adipic acid, ascorbic acid, citric acid, fumaric acid,malic acid, succinic acid or tartaric acid. Especially preferred acidsare fumaric acid and succinic acid. The diltiazem component and organicacid are preferably present in a ratio of from 10:1 to 2:1, moreespecially 6:1 to 3:1.

The core also optionally contains a lubricant which is represented byone or more of the following: sodium stearate, magnesium stearate,stearic acid or talc. The diltiazem and lubricant are preferably presentin a ratio of from 0.5:1 to 45:1.

Preferably, the core comprises diltiazem or a pharmaceuticallyacceptable salt thereof and the associated organic acid and optionallythe lubricant embedded in a polymeric material. The diltiazem componentand polymeric material are preferably present in a ratio of from 1:1 to100:1, more particularly from 5:1 to 30:1. The polymeric material may berapidly soluble in water or, alternatively, may be freely permeable todiltiazem and water.

The term water soluble polymer as used herein includes polymers whichare freely permeable to water such as Eudragit RL. Likewise, the termwater insoluble polymer as used herein includes polymers which areslightly permeable to water such as Eudragit RS.

The polymeric material preferably consists solely of a water solublepolymer or a polymer which is freely permeable to diltiazem and water.Alternatively, the polymeric material of the core may include a minorproportion of a water insoluble polymer or a polymer which is slightlypermeable to diltiazem and water. The ratio of water soluble/freelypermeable to water insoluble/slightly permeable polymer is determined bythe particular combination of polymers selected. However, in the case ofa core including a water soluble polymer and a water insoluble polymer,the ratio of water soluble polymer to water insoluble polymer willnormally be in the range of 1:1 to 50:1, more especially 3:1 to 9:1.

The water soluble polymer is suitably polyvinyl alcohol,polyvinylpyrrolidone, methyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, polyethylene glycol or a mixture thereof.An especially preferred water soluble polymer is polyvinylpyrrolidone

A suitable polymer which is freely permeable to diltiazem and water is apolymer sold under the Trade Mark EUDRAGIT RL.

The water insoluble polymer of the core is preferably selected fromethylcellulose, cellulose acetate, cellulose propionate (lower, mediumor higher molecular weight), cellulose acetate propionate, celluloseacetate butyrate, cellulose acetate phthalate, cellulose triacetate,poly(methyl methacrylate), poly(ethyl methacrylate), poly (butylmethacrylate), poly (isobutyl methacrylate), poly (hexyl methacrylate),poly (isodecyl methacrylate), poly (lauryl methacrylate), poly (phenylmethacrylate), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate), poly (octadecyl acrylate), poly(ethylene),poly(ethylene) low density, poly(ethylene) high density,poly(propylene), poly(ethylene oxide), poly(ethylene terephthalate),poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) orpolyurethane or a mixture thereof.

A suitable polymer which is slightly permeable to diltiazem and water isa polymer sold under the Trade Mark EUDRAGIT RS or a polymer whosepermeability is pH dependent and sold under the Trade Mark EUDRAGIT L,EUDRAGIT S or EUDRAGIT E.

EUDRAGIT polymers are polymeric lacquer substances based on acrylatesand/or methacrylates.

Polymeric materials sold under the Trade Marks EUDRAGIT RL and EUDRAGITRS are acrylic resins comprising copolymers of acrylic and methacrylicacid esters with a low content of quaternary ammonium groups and aredescribed in the "EUDRAGIT RL/RS" brochure of Messrs. Roban Pharma GmbH(1985) wherein detailed physical-chemical data of these products aregiven. The ammonium groups are present as salts and give rise to thepermeability of the lacquer films. EUDRAGIT RL and RS are freelypermeable (RL) or slightly permeable (RS), respectively, independent of

EUDRAGIT L is an anionic polymer synthesized from methacrylic acid andmethacrylic acid methyl ester. It is insoluble in acids and pure water.It becomes soluble in a neutral to weakly alkaline milieu by formingsalts with alkalis. The permeability of EUDRAGIT L is pH dependent.Above pH 5.0, the polymer becomes increasingly permeable. EUDRAGIT L isdescribed in the "EUDRAGIT L" brochure of Messrs. Rohm Pharma GmbH(1986) wherein detailed physical-chemical data of the product are given.EUDRAGIT E and S are also described in the "EUDRAGIT E" and "EUDRAGIT S"brochures of Messrs. Rohm Pharma GmbH (1986).

The core suitably has between 50 and 200 layers of the core-formingmaterials and is built up in a manner known per se.

Preferably, the multi-layer arrangement of diltiazem, organic acid andpolymeric material is built up on a central inert core, suitablyconsisting of a non-pareil seed of sugar/starch having an averagediameter in the range 0.4-0.8 mm, especially 0.5-0.6 mm, in aconventional coating pan. Alternatively, the diltiazem, organic acid andpolymeric material may be built up on a central inert core ashereinbefore defined in an automated coating system, for example, a CFgranulator.

The core may also include further components to those specified abovesuch as a dispersing agent, a glidant and/or a surfactant.

The diltiazem, organic acid and optional other components are blended toform a homogenous powder. The blend is suitably passed through anappropriate mesh screen, preferably a No. 50 mesh screen, using amilling machine. In the case of coating in a conventional coating pan,alternate layers of a coating solution/suspension of the polymericmaterial and the powder are applied to the central inert core so as tobuild up the multi-layer arrangement of the active core.

In accordance with a preferred feature of the present invention thecoating solution/suspension of the polymeric material and the powder areapplied simultaneously, using an automatic coating system. The coatingsolution/suspension of the polymeric material comprises one or morepolymers dissolved/suspended in a suitable solvent or mixture ofsolvents. The concentration of the polymeric material in the coatingsolution/suspension is determined by the viscosity of the finalsolution/suspension. Preferably, between 10 and 40 parts of inert coresare used relative to the homogenous powder. The addition of aplasticizing agent to the polymeric solution/suspension may be necessarydepending on the formulation to improve the elasticity and also thestability of the polymer film and to prevent changes in the polymerpermeability over prolonged storage. Such changes could affect the drugrelease rate. Suitable plasticizing agents include polyethylene glycol,propylene glycol, glycerol, triacetin, dimethyl phthalate, diethylphthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate,tributyl citrate, triethyl acetyl citrate, castor oil and varyingpercentages of acetylated monoglycerides.

Preferred coating materials include

solutions/suspensions of the polymers cited for use in the applicationof the powder blend to the central inert core in a suitableorganic/aqueous carrier medium.

The membrane of the film-forming polymer or mixture of polymerssurrounding the core preferably has a major proportion of a waterinsoluble polymer and a minor proportion of a water soluble polymer, theratio of water insoluble to water soluble polymer being determined bythe inherent solubility characteristics of the polymers selected.

The membrane may also be composed of a proportion of a polymer which isslightly permeable to diltiazem and water and a proportion of a polymerwhich is freely permeable to diltiazem and water, the ratio of slightlypermeable to freely permeable polymer being determined by the inherentpermeability of the respective polymers. The terms "water soluble" and"water insoluble" polymer embrace such polymers as indicated above.

A suitable combination of a polymer which is slightly permeable todiltiazem and water and a polymer which is freely permeable to diltiazemand water is EUDRAGIT RS and EUDRAGIT RL in a ratio of from 1:1 to 50:1,especially 2:1 to 10:1. The membrane may also include a combination ofwater soluble/water insoluble polymers and polymers which are freelypermeable/slightly permeable to diltiazem and water.

The membrane may also comprise a mixture of polymers that are watersoluble, freely permeable, water insoluble, slightly permeable andpolymers whose permeability/solubility is affected by pH.

Especially suitable polymers for the membrane include:

Polyvinylpyrrolidone, ethylcellulose, Eudragit RL, Eudragit L, EudragitE, Eudragit S, cellulose acetate and polyvinylalcohol. Commerciallyavailable ready-made polymeric solutions/suspensions are also especiallypreferred. These ready-made solutions/suspensions may optionally containplasticizing agents to improve the polymer film as described previously.Examples of ready-made solutions/suspensions of polymeric material withor without plasticizing agent include Eudragit RL 30D, Eudragit L 30D,Eudragit E 12.5, Eudragit L 12.5 Eudragit E 12.5, Eudragit RL 12.5,Eudragit RS 12.5, (Eudragit being a Trade Mark of Rohm and Haas, whosetechnical brochures describe the differences between the products),Aquacoat (a Trade Mark of FMC Corporation) and Sure-lease (a Trade Markof Colorcon Inc.).

The membrane may be built up by applying a plurality of coats ofmembrane polymer solution or suspension to the core as hereinafterdescribed. The membrane solution or suspension contains the polymer(s)dissolved or suspended, respectively, in a suitable aqueous or organicsolvent or mixture of solvents, optionally in the presence of alubricant. Suitable lubricants are talc, stearic acid, magnesiumstearate and sodium stearate. A particularly preferred lubricant istalc. The membrane polymer or mixture of polymers may optionally includea plasticizing agent, the function and choice of which has beenpreviously described.

Preferably, the number of coats of membrane solution or suspensionapplied is between 20 and 600. The dissolution rate achieved isproportionally slower as the number of membrane coats increases.

The membrane solution or suspension may be applied to the active coresin a conventional coating pan as indicated or, alternatively, using anautomated system such as a CF granulator, for example a FREUND CFgranulator, a GLATT fluidized bed processor, an AEROMATIC, a modifiedACCELA-COTA or any other suitably automated bead coating equipment(FREUND, GLATT, AEROMATIC and ACCELA-COTA are all Trade Marks).

Preferably, 2-25 ml of membrane solution/suspension is applied per coatper kilogram of active cores. In an automated system the total amount ofmembrane solution/suspension applied to the active cores is the same asthat applied in a conventional coating pan, except that the membranesolution/suspension is applied continuously.

Preferably, when a coating pan is used the membrane is applied at a rateof 20-30 coats between each drying step until all of the coats have beenapplied. Between applications the pellets are dried for between 12 and18 hours at a temperature of 50°-60° C., most suitably 55° C.

In an automated system a similar number of coats are applied betweendrying steps. However, the automated system permits such applicationover a period of only 0.25 to 3 hours, thus permitting much greaterefficiencies in production. After each application of this amount ofmembrane solution/suspension, the pellets are dried at the temperatureand for the length of time specified for coating in a coating pan.

In an automated coating system the rate of application of membranesolution/suspension is suitably 0.5-10 g/kg of cores/min. The rate ofapplication of lubricant such as talc is also suitably 0.5-10 g/kg ofcores/min. The pellets may be filled into hard or soft gelatinecapsules. The pellets may also be compressed into tablets using a binderand/or hardening agent commonly employed in tabletting such asmicrocrystalline cellulose sold under the Trade Mark "AVICEL" or aco-crystallised powder of highly modified dextrins (3% by weight) andsucrose sold under the Trade Mark "DI-PAC" in such a way that thespecific dissolution rate of the pellets is maintained.

BRIEF DESCRIPTION OF THE DRAWINGS

In the accompanying Drawings:

FIG. 1 is a graph of plasma levels (ng/ml) of diltiazem versus timeafter administration (hours) for the diltiazem formulation prepared inExample 1 (curve a) compared with a diltiazem formulation prepared inaccordance with our Patent Application No. 3057/83 (curve b);

FIG. 2 is a graph of plasma levels (ng/ml) of diltiazem versus timeafter administration (hours) for the diltiazem formulation prepared inExample 2 (curve a) compared with a diltiazem formulation prepared inaccordance with U.S. patent application Ser. No. 684,661 U.S. Pat. No.4,721,619 (curve b);

FIG. 3 is a graph of plasma levels (ng/ml) of diltiazem versus timeafter administration (hours) for the diltiazem formulation prepared inExample 3 (curve a) compared with conventional tablets (curve b);

FIG. 4 is a graph of dissolution (%) versus time (hours) of a batch ofpellets prepared in accordance with Example 3, stored under ambientconditions as hereinafter described, and tested at different times aftermanufacture.

FIG. 5 is a graph of dissolution (%) versus time (hours) of a batch ofpellets prepared in accordance with Example 3, `stored` underaccelerated conditions as hereinafter described and tested at differenttimes after manufacture.

FIG. 6 is a graph of dissolution (%) versus time (hours) of a batch ofpellets prepared in accordance with Example 1 of U.S. Patent ApplicationSerial No. 684,661, U.S. Pat. No. 4,721,619, `stored` under acceleratedconditions as hereinafter described, and tested at different times aftermanufacture.

The invention will be further illustrated by the following Examples:

EXAMPLES

Diltiazem hydrochloride (10.0 kg), fumaric acid (2.5 kg) and talc (1.0kg) were blended and milled through a No. 50 mesh screen so as to obtaina homogenous powder.

The powder was applied to starch/sugar seeds (0.6-0.71 mm diameter) (5.0kg) in a standard coating pan using a coating solution of:

    ______________________________________                                        10% Polyvinylpyrrolidone in isopropanol                                                                  75     parts                                        5% Ethylcellulose in methanol/methylene                                                                 20     parts                                       chloride 50/50                                                                 5% Polyvinylchloride in acetone                                                                         4.5    parts                                       Dibutyl phthalate          0.1    parts                                       ______________________________________                                    

The seeds were coated with a measured volume of coating solutionfollowed by dusting on of a measured weight of the powder mix. Thecoated seeds were allowed to dry and the coating step repeated until allof the powder had been applied. The coated seeds were then dried at 45°C. overnight.

The coated seeds defining the active core of the pellet being preparedwere then surrounded by an outer membrane consisting of:

    ______________________________________                                        5% Eudragit RS in acetone/isopropanol                                                                    80     parts                                       5% Eudragit RL in acetone/isopropanol                                                                    15     parts                                       5% Polyvinylchloride in acetone                                                                          5      parts                                       Talc                       99     parts                                       Dibutyl phthalate          1      part                                        ______________________________________                                    

A volume equivalent to 5 ml per kg of coated seeds was applied to theseeds in a standard coating pan. After each coat had been applied thepellets were air dried in the coating pan.

At regular intervals the pellets were placed in an oven and allowed todry for more than twelve hours.

The pellets were then returned to the coating pan and the process ofcoating, followed by drying to remove solvents, was continued.

The finished pellets were then subjected to a dissolution test. Thedissolution rate of the pellets was tested by the method of U.S.Pharmacopoeia XXI (Paddle Method) in 0.05 M KCl adjusted to pH 7.0 andwas found to be as follows:

    ______________________________________                                                     Diltiazem hydrochloride                                          Time (hours) % Released                                                       ______________________________________                                        2            8.7                                                              6            62.8                                                             13           92.0                                                             ______________________________________                                    

EXAMPLE 2

Example 1 was repeated except starch/sugar seeds 0.5-0.6 mm were used.

The coating solution used was:

    ______________________________________                                        17.5% Polyvinylpyrrolidone in isopropanol                                                                90     parts                                       10.0% Cellulose acetate in methylene chloride                                                            10     parts                                       The membrane suspension used was:                                             12.5% Eudragit RS in acetone/isopropanol                                                                 90     parts                                       12.5% Eudragit RL in acetone/isopropanol                                                                 10     parts                                       Talc                       100    parts                                       Isopropanol                100    parts                                       ______________________________________                                    

At regular intervals the pellets were placed in an oven and dried at 55°C. for more than twelve hours to remove solvents as in Example 1. Thedissolution rate was tested according to the U.S. Pharmacopoeia XXI(Paddle Method). The results were as follows:

    ______________________________________                                                     Diltiazem hydrochloride                                          Time (hours) % Released                                                       ______________________________________                                        2            28.0                                                             6            69.0                                                             13           94.0                                                             ______________________________________                                    

EXAMPLE 3

Diltiazem hydrochloride (40 kg), fumaric acid (5 kg) and talc (4.0 kg)were blended and milled through a No. 50 mesh screen so as to obtain ahomogenous powder.

The powder so obtained was applied to starch/sugar seeds (20 kg) 0.5-0.6mm in diameter, in a FREUND CF granulator using a coating solution of:

9.0% Polyvinylpyrrolidone in isopropanol

The seeds were coated with a measured volume of coating solutionfollowed by dusting on of a measured weight of the powder mix. Thecoated seeds were allowed to dry and the coating step repeated until allof the powder had been applied. The coated seeds were then dried at 55°C. overnight to remove solvent.

The coated seeds defining the active core of the pellet being preparedwere then surrounded by an outer membrane. The membrane suspension usedwas:

    ______________________________________                                        12.5% Eudragit RS in acetone/isopropanol                                                                 80     parts                                       12.5% Eudragit RL in acetone/isopropanol                                                                 20     parts                                       Talc                       100    parts                                       Isopropanol                100    parts                                       ______________________________________                                    

The seeds were then coated in a CF granulator with the membranesuspension and dried at regular intervals at 55° C. for 16 hours toremove solvents.

The finished pellets were then subjected to a dissolution test. Thedissolution rate of the pellets was tested by the method of U.S.Pharmacopoeia XXI (Paddle Method) in 0.05 M KCl adjusted to pH 7.0 andwas found to be as follows:

    ______________________________________                                                     Diltiazem hydrochloride                                          Time (hours) % Released                                                       ______________________________________                                        2            22.3                                                             6            65.4                                                             13           88.0                                                             ______________________________________                                    

EXAMPLE 4

Diltiazem hydrochloride (3.0 kg), succinic acid (0.5 kg) and talc (0.3kg) were blended and milled through a No. 50 mesh screen so as to obtaina homogenous powder.

The powder was applied to starch/sugar seeds (0.6-0.71 mm diameter)(0.75 kg) in a standard coating pan using a coating solution of:

    ______________________________________                                        9% Polyvinylpyrrolidone in isopropanol                                                                   100    parts                                       ______________________________________                                    

The active cores of the pellet being prepared were then surrounded by amembrane by applying coats of a suspension consisting of:

    ______________________________________                                        12.5% EUDRAGIT RS in acetone/isopropanol                                                                 2      parts                                       40:60                                                                         12.5% EUDRAGIT RL in acetone/isopropanol                                                                 20     parts                                       40:60                                                                         12.5% EUDRAGIT L in acetone/isopropanol 40:60                                                            10     parts                                       Talc                       49     parts                                       Dimethyl phthalate         1      part                                        ______________________________________                                    

After each coat had been applied the pellets were air dried in thecoating pan. At regular intervals the pellets were placed in an oven anddried at 55° C. for more than twelve hours to remove solvent as inExample 1.

Finished pellets were then subjected to a dissolution test. Thedissolution rate of the pellets was tested by the method of the U.S.Pharmacopoeia XXI (Paddle Method) in 0.05 M KCl at pH 7.0 at 100 r.p.m.

The dissolution rate was as follows:

    ______________________________________                                                     Diltiazem hydrochloride                                          Time (hours) % Released                                                       ______________________________________                                        2            18.9                                                             6            63.4                                                             13           89.6                                                             ______________________________________                                    

EXAMPLE 5

Diltiazem hydrochloride (40 kg), fumaric acid (10 kg) and talc (4 kg)were blended and milled through a No. 50 mesh screen.

The powder was applied to starch/sugar seeds (0.5-0.6 mm diameter) witha FREUND CF granulator using a coating solution of:

    ______________________________________                                         8% Polyvinylpyrrolidone in ethanol                                                                      90     parts                                       10% Ethocel (Ethocel is a Trade Mark) in                                                                 9.8    parts                                       isopropanol                                                                   Diethyl phthalate          0.2    parts                                       A membrane was then applied to the active cores by                            spraying on a suspension consisting of:                                       12.5% EUDRAGIT RL in acetone/isopropanol                                                                 10     parts                                       40:60                                                                         12.5% EUDRAGIT RS in acetone/isopropanol                                                                 40     parts                                       40:60                                                                         Isopropanol                48.75  parts                                       Tributyl citrate           1.25   parts                                       ______________________________________                                    

While simultaneously but separately dusting on talc (100 parts byweight) in conventional manner.

A sufficient amount of membrane suspension and talc was applied toachieve a dissolution rate of the pellets, when measured according toU.S. Pharmacopoeia XXI (Paddle Method) as per the previous Examples, asfollows:

    ______________________________________                                                     Diltiazem hydrochloride                                          Time (hours) % Released                                                       ______________________________________                                        2            24.3                                                             6            71.6                                                             13           98.3                                                             ______________________________________                                    

EXAMPLE 6

Example 4 was repeated except the application solution consisted of:

    ______________________________________                                         5% Hydroxypropylmethyl cellulose in                                                                     99     parts                                       methanol/methylene chloride                                                   Propylene glycol           1      part                                        and the membrane suspension used was                                          10% Cellulose acetate in acetone                                                                         90     parts                                        5% Polyethylene glycol in acetone                                                                       10     parts                                       Talc was added as per Example 4.                                              ______________________________________                                    

A sufficient quantity of membrane suspension was applied to the pelletsto achieve the following dissolution rate, all pellets having been driedto remove solvents.

    ______________________________________                                                     Diltiazem hydrochloride                                          Time (hours) % Released                                                       ______________________________________                                        2            13.8                                                             6            61.3                                                             13           88.6                                                             ______________________________________                                    

Pharmacological Data for the Diltiazem Formulation of Example 1

A single-dose crossover study was performed in 6 young healthy malesubjects comparing the formulation of Example 1 against the formulationof Example 1 of U.S. patent application Ser. No. 684,661, U.S. Pat. No.4,721,619 (hereinafter referred to as Reference). Both the formulationof Example 1 and the Reference formulation were administered as a singleencapsulated dose of 120 mg at 0 hours. Plasma concentration ofdiltiazem was determined at intervals over 24 hours and the results aregiven in Table 1. Pharmacokinetic data are given in Table 2.

                  TABLE 1                                                         ______________________________________                                        MEAN DILTIAZEM PLASMA CONCENTRATIONS (ng/ml)                                  Time (hours)                                                                              Reference Formulation of Example 1                                ______________________________________                                        0.00        0.0       0.0                                                     1.00        0.00      0.00                                                    2.00        2.75      1.87                                                    4.00        25.35     40.67                                                   5.00        36.83     53.00                                                   6.00        47.67     56.33                                                   7.00        56.50     61.33                                                   8.00        63.17     66.50                                                   9.00        64.33     63.50                                                   10.00       62.17     64.67                                                   12.00       50.50     51.50                                                   14.00       43.50     41.67                                                   16.00       30.33     29.00                                                   18.00       24.17     23.50                                                   20.00       12.42     20.07                                                   24.00       12.42     14.52                                                   ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                        PHARMACOKINETIC EVALUATION (n = 6)                                            Parameters Reference Formulation of Example 1                                 ______________________________________                                        AUC (0-∞)                                                                          897.33    965.33                                                   F (∞) %                                                                            100       111.73                                                   tmax       9.83      8.17                                                     Cmax       68.50     70.50                                                    t 1/2      6.43      9.13                                                     ______________________________________                                    

FIG. 1 is a graph of plasma levels (ng/ml) of diltiazem versus timeafter administration (hours) for a single dose (120 mg) of the diltiazemformulation prepared in Example 1 (curve a) compared with a single dose(120 mg) of the Reference formulation (curve b). As will be appreciated,the data for the Reference formulation was obtained from a differentgroup of subjects to that of present Example 1, thus making anycomparison of bioavailability purely indicative. It will be observedfrom FIG. 1 that a virtually identical absorption pattern is obtainedfor each formulation, consistent with twice-daily administration. Henceit is submitted the actual bioavailability values would have beensimilar if the two formulations had been tested in the same subjects.

Pharmacological Data for the Diltiazem Formulation of Example 2

A single-dose crossover study was performed in 6 young healthy malesubjects comparing the formulation of Example 2 against the formulationof Example 1 of U.S. patent application Ser. No. 684,661, U.S. Pat. No.4,721,619 (hereinafter referred to as Reference). Both formulations wereadministered as a single 120 mg capsule at 0 hours. Plasma concentrationof diltiazem was determined at intervals over 24 hours and the resultsare given in Table 3. Pharmacokinetic data is given in Table 4.

                  TABLE 3                                                         ______________________________________                                        MEAN DILTIAZEM PLASMA CONCENTRATIONS (ng/ml)                                  Time (hours)                                                                              Reference Formulation of Example 2                                ______________________________________                                        0.00        0.0       0.0                                                     1.00        0.00      0.00                                                    2.00        2.17      2.18                                                    4.00        29.67     49.50                                                   5.00        52.33     68.00                                                   6.00        63.67     75.33                                                   7.00        69.00     74.17                                                   8.00        69.50     67.00                                                   9.00        62.50     58.50                                                   10.00       53.83     48.50                                                   12.00       38.67     35.83                                                   14.00       27.17     31.83                                                   16.00       20.17     19.83                                                   18.00       15.22     15.42                                                   20.00       12.95     10.97                                                   24.00       7.70      6.53                                                    ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        PHARMACOKINETIC EVALUATION (n = 6)                                            Parameters Reference Formulation of Example 2                                 ______________________________________                                        AUC (0-∞)                                                                          769.75    793.44                                                   F (∞) %                                                                            100.00    110.00                                                   tmax       7.17      6.17                                                     Cmax       76.33     81.50                                                    t 1/2      5.06      4.56                                                     ______________________________________                                    

FIG. 2 is a graph of plasma levels (ng/ml) of diltiazem versus timeafter administration (hours) for a single dose (120 mg) of the diltiazemformulation prepared in Example 2 (curve a) compared with a single dose(120 mg) of the Reference formulation (curve b). As in the case of thepharmacological data for the formulation of Example 1 compared with theReference, the data for the reference formulation were obtained from adifferent group of subjects to that of present Example 2, thus makingany comparison of bioavailability purely indicative. It will be observedfrom FIG. 2 that a virtually identical absorption pattern is obtainedfor each formulation, consistent with twice-daily administration. Henceit is submitted the actual bioavailability values would have beensimilar if the two formulations had been tested in the same subjects.

Pharmacological Data for the Diltiazem Formulation of Example 3

A steady-state crossover study was performed in 12 young healthy malesubjects comparing the formulation of Example 3 against conventionalimmediate release tablets (Reference tablets),

The formulation of Example 3 was administered as a single 120 mg capsuleat 0 and 12 hours (b.i.d.), while the Reference was administered as asingle 60 mg tablet at 0, 6, 12 and 18 hours (q.i.d.). Plasmaconcentration of diltiazem was measured at intervals over 24 hours onDay 5 and the results are given in Table 5. Pharmacokinetic data aregiven in Table 6.

                  TABLE 5                                                         ______________________________________                                        MEAN DILTIAZEM PLASMA CONCENTRATIONS (ng/ml)                                  (Day 5)                                                                                   Reference                                                         Time (hours)                                                                              Tablets   Formulation of Example 3                                ______________________________________                                        0.00        81.83     78.50                                                   0.50        85.50     --                                                      1.00        121.25    87.83                                                   2.00        153.42    100.75                                                  3.00        166.00    --                                                      4.00        140.17    125.42                                                  6.00        90.67     118.00                                                  6.50        78.33     --                                                      7.00        96.92     109.67                                                  8.00        121.83    98.92                                                   9.00        126.33    89.92                                                   10.00       103.08    82.08                                                   12.00       71.08     70.17                                                   12.50       62.17     --                                                      13.00       75.75     --                                                      14.00       88.17     70.75                                                   15.00       104.92    --                                                      16.00       99.83     83.92                                                   18.00       73.17     93.50                                                   18.50       65.25     --                                                      19.00       81.67     --                                                      20.00       103.92    98.00                                                   21.00       112.00    --                                                      22.00       108.33    --                                                      24.00       82.00     86.00                                                   ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                        PHARMACOKINETIC EVALUATION (n = 6)                                                       Reference                                                          Parameters Tablets   Formulation of Example 3                                 ______________________________________                                        AUC (0-24h)                                                                              2474.88   2230.33                                                  F (t) %    100.00     90.96                                                   Cmax       172.08    130.42                                                   tmax        2.75      4.17                                                    ______________________________________                                    

FIG. 3 is a graph of plasma levels (ng/ml) of diltiazem versus timeafter administration (hours) for a single dose (120 mg) of the diltiazemformulation prepared in Example 3 (curve a) compared with a single dose(60 mg) of reference tablets administered as indicated above.

It will be observed from the data presented in Table 6 that theformulation of Example 3 is 90.96% bioavailable compared to reference(=100%), and has a quite similar Cmax and AUC (0-24h). However, theformulation of Example 1 has extended tmax (4.17 hours compared to 2.75hours for Reference) which satisfies the criteria for controlledabsorption orally administered drugs, and further shows a reduction inpeak-to-trough fluctuations as indicated in FIG. 3.

Experiments were carried out to assess the stability of the pelletformulation according to the invention relative to formulations of U.S.patent application Ser. No. 684,661, U.S. Pat. No. 4,721,619.

Dissolution tests of the type described in Example 1 were carried out ona batch of the pellet formulation of Example 3 after storage in ambientconditions over a period concomitant with commercial shelf-life, inaccordance with established criteria. The results are presented in FIG.4 which is a graph of dissolution (%) versus time (hours) taken at threedifferent time points after manufacture of the formulation of Example 3under the indicated conditions and is indicative of the stability of theformulation under these conditions. In FIG. 4 curve a represents thebatch as tested after 3 months of storage, curve b the batch as testedafter 6 months of storage and curve c the batch as tested after 18months of storage.

Dissolution tests of the type described in Example 1 were also carriedout on a batch of the pellet formulation of Example 3 under `acceleratedconditions` (37° C. and 75% relative humidity) in accordance withestablished criteria. The results are presented in FIG. 5 which is agraph of dissolution (%) versus time (hours) taken at three differenttime points after the manufacture of the formulation of Example 3 underthe indicated conditions and is indicative of the stability of theformulation under these conditions. In FIG. 5 curve a represents thebatch as tested after 1 month of storage, curve b the batch as testedafter 3 months of storage and curve c the batch as tested after 6 monthsof storage.

Identical dissolution tests under identical accelerated conditions werecarried out on a batch of a pellet formulation prepared in accordancewith Example 1 of U.S. patent application Ser. No. 684,661, U.S. Pat.No. 4,721,619. The results are presented in FIG. 6 which again is agraph of dissolution (%) versus time (hours) taken at three differenttime points after the manufacture of the formulation in question. InFIG. 6 curve a represents the batch as tested after 1 month of storage,curve b the batch as tested after 3 months of storage and curve thebatch as tested after 6 months of storage. A comparison of FIGS. 4, 5and 6 demonstrates the stability of the formulation of the presentinvention relative to the formulation of U.S. patent application Ser.No. 684,661 U.S. Pat. No. 4,721,619 as indicated by the error bars whichrepresent the dissolution specifications for each of the formulations.As will be observed the formulation of U.S. patent application Ser. No.684,661 U.S. Pat. No. 4,721,619 under the specified conditions isunstable and therefore if commercially used would require excessiveinventory control procedures.

The formulation according to the invention, which is characterised by aspecific in vitro dissolution rate and a more controlled manufacturingprocess, has excellent stability over the normal marketing shelf-life(18 months to 2 years) in terms of both in vivo and in vitroperformance.

We claim:
 1. A method of controlling or preventing angina attacks orreducing the incidence of angina attacks in a subject suffering fromangina pectoris, comprising administering to said subject on a once per12 hour basis a dose effective to improve the blood supply and henceincrease the oxygen supply in the myocardium of said subject throughoutsaid 12 hour period, of a diltiazem containing controlled absorptionpellet formulation, said pellet comprising a core of diltiazem or apharmaceutically acceptable salt thereof in association with an organicacid, said core surrounded by a multi-layered polymeric membrane, eachlayer containing a major proportion of a pharmaceutically acceptablefilm-forming, water insoluble synthetic polymer and a minor proportionof a pharmacetutically acceptable film-forming water soluble syntheticpolymer, the ratio of said diltiazem to organic acid and the ratio ofwater insoluble polymer to water soluble polymer being effective toprovide peak myocardium oxygenating levels int eh blood 4 to 12 hoursfollowing administration.
 2. The method of claim 1 wherein the ratio ofthe diltiazem component and the organic acid is from about 19:1 to 1:1.3. The method of claim 1 wherein a plurality of pellets are administeredin capsule form.
 4. The method of claim 1 wherein a plurality of pelletsare administered in tablet form.